JPS6361000B2 - - Google Patents
Info
- Publication number
- JPS6361000B2 JPS6361000B2 JP54006603A JP660379A JPS6361000B2 JP S6361000 B2 JPS6361000 B2 JP S6361000B2 JP 54006603 A JP54006603 A JP 54006603A JP 660379 A JP660379 A JP 660379A JP S6361000 B2 JPS6361000 B2 JP S6361000B2
- Authority
- JP
- Japan
- Prior art keywords
- culture
- dione
- hours
- pregnene
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 241000223208 Curvularia Species 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims description 2
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 238000000855 fermentation Methods 0.000 description 20
- 230000004151 fermentation Effects 0.000 description 20
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 14
- 239000000758 substrate Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 241000223211 Curvularia lunata Species 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 150000003431 steroids Chemical class 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000005909 Kieselgur Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 6
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 6
- 239000008174 sterile solution Substances 0.000 description 6
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 5
- 206010015150 Erythema Diseases 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 4
- 241000203720 Pimelobacter simplex Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 231100000321 erythema Toxicity 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000134727 Agromyces mediolanus Species 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 206010047139 Vasoconstriction Diseases 0.000 description 3
- HPAKILCZTKWIFK-JZTHCNPZSA-N [2-[(8r,9s,10r,13s,14s,17r)-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2 HPAKILCZTKWIFK-JZTHCNPZSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000025033 vasoconstriction Effects 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- HOMDJHGZAAKUQV-UHFFFAOYSA-N 1-(propoxymethoxy)propane Chemical compound CCCOCOCCC HOMDJHGZAAKUQV-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000186063 Arthrobacter Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 206010033546 Pallor Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- QCGGRRYKXPSMLE-LJHIYBGHSA-N [2-[(8r,9s,10r,13s,14s,17r)-10,13-dimethyl-3-oxo-17-(propoxymethoxy)-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(C)=O)(OCOCCC)[C@@]1(C)CC2 QCGGRRYKXPSMLE-LJHIYBGHSA-N 0.000 description 2
- IPIRNZTZVZJJNU-WYKXONHLSA-N [2-[(8r,9s,10r,13s,14s,17r)-17-(ethoxymethoxy)-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(C)=O)(OCOCC)[C@@]1(C)CC2 IPIRNZTZVZJJNU-WYKXONHLSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- -1 fatty acid esters Chemical class 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000002906 microbiologic effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QLCJOAMJPCOIDI-UHFFFAOYSA-N 1-(butoxymethoxy)butane Chemical compound CCCCOCOCCCC QLCJOAMJPCOIDI-UHFFFAOYSA-N 0.000 description 1
- FCYQTGCEDUOHLT-LEKSSAKUSA-N 1-[(8s,9s,10r,13s,14s,17s)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl]ethanone Chemical compound C1C=C2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 FCYQTGCEDUOHLT-LEKSSAKUSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 1
- WDEVXRIFJZNMKM-UHFFFAOYSA-N 2-(propan-2-yloxymethoxy)propane Chemical compound CC(C)OCOC(C)C WDEVXRIFJZNMKM-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000193422 Bacillus lentus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 241001040638 Curvularia eragrostidis Species 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical class C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000589565 Flavobacterium Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000193386 Lysinibacillus sphaericus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- ISNRHKLDVGKVAC-HRKNWXKCSA-N [2-[(6s,8r,9s,10r,13s,14s,17r)-6-fluoro-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@](C(=O)COC(=O)C)(O)[C@@]2(C)CC1 ISNRHKLDVGKVAC-HRKNWXKCSA-N 0.000 description 1
- NJCVKKDFYOBRML-LJHIYBGHSA-N [2-[(8r,9s,10r,13s,14s,17r)-10,13-dimethyl-3-oxo-17-(propan-2-yloxymethoxy)-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(C)=O)(OCOC(C)C)[C@@]1(C)CC2 NJCVKKDFYOBRML-LJHIYBGHSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
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- 239000003470 adrenal cortex hormone Substances 0.000 description 1
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- 229910052786 argon Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
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- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
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- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
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- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940043075 fluocinolone Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N n-butyl methyl ketone Natural products CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960001917 prednylidene Drugs 0.000 description 1
- WSVOMANDJDYYEY-CWNVBEKCSA-N prednylidene Chemical group O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](C(=C)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 WSVOMANDJDYYEY-CWNVBEKCSA-N 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- RJKFOVLPORLFTN-UHFFFAOYSA-N progesterone acetate Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 RJKFOVLPORLFTN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940125379 topical corticosteroid Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0084—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkylene group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
本発明は、一般式:
〔式中〓は単結合又は二重結合を表わし、Xは水
素原子、フツ素原子、塩素原子又はメチル基を表
わし、
Wはメチレン基、エチリデン基又はビニリデン
基を表わし、
R1は炭素原子数1〜6を有するアルキル基を
表わす〕
で示される11β−ヒドロキシステロイドを製造す
るに当り、一般式XI:
〔式中X、W及びR1は前記のものを表わし、R4
はヒドロキシ基又は炭素原子数1〜6のアルカノ
イルオキシ基を表わす〕で示される11−デスオキ
システロイドを、クルブラリア属の培養菌で発酵
させ、得られた〓が単結合を表わす式の化合物
を、場合によつては1,2−位で脱水素化するこ
とを特徴とする前記11β−ヒドロキシステロイド
の製造方法に関する。
一般式で示される11β−ヒドロキシステロイ
ドは、一般式XII:
〔式中〓、X、W及びR4は一般式に関して記
載したものを表わす〕で示されるステロイドを製
造するための中間生成物として使用される。
周知のように、抗炎症作用を有する11β−ヒド
ロキシステロイド(例えばコルチコイド:ヒドロ
コーチゾン、プレドニソロン、デキサメタソン、
ベータメタソン、プレドニリデン、トリアムシノ
ロン、フルオシノロン又はフルアンドレノロン)
は、極めてコスト高な多段階部分合成で天然産ス
テロイド(例えばジオスゲニン)から製造される
が、天然産ステロイドを多量に供給するのが次第
に困難になつている。上記ステロイドの多段階合
成の内で、ステロイドの骨格に11β−ヒドロキシ
基を微生物的に導入する段階は、一般に極めて高
価で損失の多い合成段階である。
1966年、プレグナン系11−デスオキシ−17α−
ヒドロキシステロイドを11β−ヒドロキシ化する
場合、17α−ヒドロキシ基をエステル化し、次に
クルブラリア属のカビでヒドロキシル化し、得ら
れる11β−ヒドロキシ−17α−アシルオキシステ
ロイドを加水分解することによつて収量を著しく
高めうる方法が開発された(西独特許第1618599
号)。
しかし17−ヒドロキシ基のアシル化は極めてコ
スト高であり、この際得られる収量は不満足であ
ることが多い。
また11β−ヒドロキシ−17α−アシルオキシス
テロイドの加水分解も困難である、それというの
も大抵副生成物が形成され、ひいては、得られた
生成物が医薬用作用物質に必要な純度基準に相応
するためには該生成物のコスト高で損失の多い精
製が必要であるからである。
これに対して本発明による方法の場合には、相
応する17−ヒドロキシステロイドより好収率で製
造されうる出発ステロイドが使用され、得られた
生成物は迅速かつ定量的に相応する11β,17α−
ジヒドロキシステロイドに加水分解されうる。
本発明により使用されるステロイドは常法で置
換されておりかつ/又は二重結合を有していても
よい。
例えば21−位におけるヒドロキシ基又はアシル
オキシ基の存在、例えば6−位及び/又は16−位
におけるハロゲン原子、好ましくはフツ素原子、
メチル基又はメチレン基の存在は本発明による方
法の実施に影響を及ぼさない。本発明による方法
のためには出発化合物として、有利に3−位にオ
キソ基を有し、4,5−位に二重結合を有するよ
うなステロイドが使用される。
本発明による方法は、他の出発化合物を使用す
ることは別にして、普通クルブラリア属のカビに
よるステロイドの11β−ヒドロキシル化のために
用いられる条件下に実施される。
ヒドロキシル化のために適当なクルブラリア属
のカビは例えばクルブラリア・フアルクータ
(falcuta)QH−102H、クルブラリア・ゲンテイ
クラータ(genticulata)IFO(6284)、クラブラ
リア・ルナータ(lunata)NRRL2380
(ATCC12017)、NRRL2434(ATCC13633)又は
IFO(6286)又はクルブラリア・マクランス
(maculans)IFO(6292)である。
クルブラリア属のカビとして他の11β−ヒドロ
キシル化をもたらす微生物も方法実施のために適
当であると述べられている。しかしこれは一般に
は本発明による方法に対して利点をもたらさな
い。
前記微生物に関して通常使用される培養条件下
に適当な通気培養基、深部培養で増殖を行なう。
次に培養物に基質を(適当な溶剤に溶かすは又は
好ましくは乳化された形で)加えかつ最大の基質
変化が達成されるまで発酵させる。
適当な基質溶剤は、例えばメタノール、エタノ
ール、グリコールモノメチルエーテル、ジメチル
ホルムアミド又はジメチルスルホキシドである。
基質の乳化は、例えば、基質を微粒子に細砕され
た形で又は水と混合可能の溶剤(例えばメタノー
ル、エタノール、アセトン、グリコールモノエチ
ルエーテル、ジメチルホルムアミド又はジメチル
スルホキシド)に溶かして、常用の乳化助剤を含
有する(好ましくは脱灰された)水中に激しい乱
流下に噴出することによつて行なうことができ
る。適当な乳化助剤は、例えば酸化エチレン付加
物又はポリグリコールの脂肪酸エステルのような
非イオン性乳化剤である。適当な乳化剤として例
えば市販の湿潤剤テギン(Tegin商標、以下同
じ)タガート(Tagat)、ツウイン(Tween)及
びスパン(Span)が挙げられる。
基質の乳化によつて基質処理量を高め、ひいて
は基質濃度を増大させうることが多い。しかしも
ちろん本発明による方法の場合発酵業者に周知の
他の方法を用いて基質処理量を高めてもよい。
最適な基質濃度、基質添加時間及び発酵期間
は、使用される基質の構造及び使用される微生物
の種類に依存する。微生物学的ステロイド変換の
際に一般に必要とされる前記の濃度、添加時間及
び発酵期間の大きさは、個々の場合について、当
業者に周知の予備試験によつて確かめられなけれ
ばならない。
場合によつて引続き行なわれる1−位で飽和さ
れた一般式の△4−ステロイドの脱水素化は、
微生学的方法ならびに純化学的方法によつて実施
することができる。すなわち△4−ステロイドは
例えば、慣用条件下にバチルス(Bacillus)属
〔例えばバチルス・レンツス(Bacillus lentus)
又はバチルス・スフエリクス(Bacillus
sphaericus)〕又はアルトロバクテル(Arthro−
bacter)属〔例えばアルトロバクタテル・シンプ
レクス(Arthrobacter sumplex)〕の培養細菌
で1−位で脱水素化することができる。しかしま
た、△4−ステロイドを、このような反応の場合
に常用される酸化剤、例えば二酸化セレン又は
2,3−ジクロル−5,6−ジシアノベンゾキノ
ンと一緒に不活性溶剤中で加熱することによつて
△1−脱水素化を実施することもできる。
得られた方法生成物は容易に相応する11β,
17α,21−トリヒドロキシステロイドに分解する
ことができる。
この分解は、アセタールの加水分解又はアルコ
リシスのために慣用される条件下に実施される。
すなわち該化合物を例えば、メタノール又はエタ
ノールのような低級アルコール中又は水を含む有
機溶剤例えばグリコールモノメチルエーテル、テ
トラヒドロフラン、ジオキサン、ジメチルホルム
アミド、ジメチルスルホキシド、ヘキサメチルホ
スホン酸トリアミド、アセトン中で、塩酸、硫
酸、リン酸、過塩素酸のような鉱酸、p−トルオ
ールスルホン酸のようなスルホン酸、ギ酸、酢
酸、トリフルオル酢酸、酸性イオン交換体のよう
な強酸性カルボン酸又は三フツ化ホウ素、塩化亜
鉛、臭化亜鉛又は四塩化チタンのようなルイス酸
と反応させることによつて分解を行なうことがで
きる。
一般式の新規コルチコイドは局所的適用時に
極めて良好な抗炎症性作用によつて優れておりか
つ所望の局所的作用と望ましくない全身的副作用
との間の極めて有利な分離作用を有する:
局所的作用は血管収縮試験によつて測定するこ
とができる。
血管収縮試験は、最後の二週間の間コルチコス
テロイド局所療法を受けていない両性の健康な被
験者8人について実施する。被験者の背中の角質
層から透明層までを除去した(20〜40回テサフイ
ルム(Tesafilm)で剥離)後各0.1gの調剤を、
4cm2の面積の領域に被蓋繃帯なしに塗布する。同
調剤がその都度皮膚の同一部分に適用されないよ
うに順次回転しながら塗布する。
血管収縮は4時間後及び8時間後に実験者によ
つて視覚的に次の作用度により判定する:
1=完全蒼白化、2=僅かに残余紅斑あり、3
=中程度の紅斑(剥離された皮膚、未処理の皮膚
及び損傷のない皮膚の中央部における赤化強さ)、
4=明るい部分の少ない紅斑、5=蒼白化せず、
又は紅斑強化。
個々の判定を行なう。
実験の順番ごとに対照物質としてジフルオルト
ロン−21−バレリアネート(=6α,9α−ジフル
オル−11β−ヒドロキシ−16α−メチル−21−バ
レリルオキシ−1,4−プレグナジエン−3,20
−ジオン=DEV)を使用する。
個々の試験順番で得られたDEV平均作用度と
被験物質の平均作用度との差△をその都度決定す
る。プラスの偏差△はDFVと比べて被験物質が
有利であると判定されることを示し、マイナスの
偏差は同様に不利であると判定されることを示
す。
以下の表には、被験者の治療の際に作用物質
0.1ppmを含有する調剤を用いて得られる試験成
績を記載してある。
該化合物の全身的作用は補助薬による浮腫試験
によつて確定することができる:
体重130〜150gのSPFラツトに炎症性病巣をつ
くるために0.5%ミコバクテリウム・ブチリクム
(Mycobacterium butyricum)懸濁液(米国
Difko社製)0.1mlを体重130〜150gのSPFラツト
の右後脚に注射する。注射前にラツトの脚容積を
測定する。注射24時間後に再び脚容積を測定して
浮腫の程度を決定する。次に種々の量の被験物質
(安息香酸ベンジル29%とヒマシ油71%とより成
る混合物中に溶かす)をラツトに経口的又は皮下
的に適用する。更に24時間後に脚容積を再び測定
する。
対照動物も同様に処置するが、被験物質を含ま
ない安息香酸ベンジル−ヒマシ油混合物を注射す
る点が相違する。
普通、得られた脚容積から、実験的につくられ
る脚浮腫の容積を50%減少させるために必要な被
験物質の量を決定する。以下の表には得られた試
験成積が記載してあるが、本発明による物質は市
販製剤として存在する構造的に極めて類似の公知
コルチコイドと比較してある。
The present invention is based on the general formula: [In the formula] represents a single bond or double bond, X represents a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group, W represents a methylene group, an ethylidene group, or a vinylidene group, R 1 is the number of carbon atoms represents an alkyl group having 1 to 6] In producing the 11β-hydroxysteroid represented by the general formula XI: [In the formula, X, W and R 1 represent the above, and R 4
represents a hydroxy group or an alkanoyloxy group having 1 to 6 carbon atoms] is fermented with a cultured bacterium of the genus Curvularia, and the resulting compound of the formula in which 〓 represents a single bond, The present invention relates to a method for producing the 11β-hydroxysteroid, which is characterized in that dehydrogenation is carried out at the 1,2-position in some cases. The 11β-hydroxysteroid represented by the general formula is represented by the general formula XII: It is used as an intermediate product for producing steroids of the formula: where X, W and R 4 are as described for the general formula. As is well known, 11β-hydroxysteroids (e.g. corticoids: hydrocortisone, prednisolone, dexamethasone,
betamethasone, prednylidene, triamcinolone, fluocinolone or fluandrenolone)
are produced from naturally occurring steroids (e.g. diosgenin) in an extremely costly multi-step partial synthesis, but it is becoming increasingly difficult to supply naturally occurring steroids in large quantities. In the multi-step synthesis of steroids, the step of microbially introducing an 11β-hydroxy group into the steroid skeleton is generally an extremely expensive and lossy synthetic step. 1966, Pregnane series 11-desoxy-17α-
When 11β-hydroxylating hydroxysteroids, the yield can be significantly increased by esterifying the 17α-hydroxy group, then hydroxylating with Curvularia mold, and hydrolyzing the resulting 11β-hydroxy-17α-acyloxysteroid. A method was developed (West German Patent No. 1618599)
issue). However, acylation of 17-hydroxy groups is extremely expensive and the yields obtained are often unsatisfactory. The hydrolysis of 11β-hydroxy-17α-acyloxysteroids is also difficult, since by-products are usually formed and thus the products obtained do not meet the purity standards required for pharmaceutical active substances. necessitates costly and lossy purification of the product. In contrast, in the process according to the invention, starting steroids are used which can be prepared in better yields than the corresponding 17-hydroxysteroids, and the products obtained can be quickly and quantitatively determined from the corresponding 11β,17α-
Can be hydrolyzed to dihydroxysteroids. The steroids used according to the invention may be substituted in the conventional manner and/or contain double bonds. the presence of a hydroxy group or an acyloxy group, e.g. in the 21-position, a halogen atom, preferably a fluorine atom, in the 6-position and/or the 16-position,
The presence of methyl or methylene groups does not affect the performance of the process according to the invention. Steroids which preferably have an oxo group in the 3-position and a double bond in the 4,5-position are used as starting compounds for the process according to the invention. The process according to the invention, apart from using other starting compounds, is carried out under the conditions normally used for the 11β-hydroxylation of steroids by molds of the genus Curvularia. Suitable molds of the genus Curvularia for hydroxylation are, for example, Curvularia falcuta QH-102H, Curvularia genticulata IFO (6284), Curvularia lunata NRRL2380.
(ATCC12017), NRRL2434 (ATCC13633) or
IFO (6286) or Curvularia maculans IFO (6292). Other 11β-hydroxylation-producing microorganisms, such as molds of the genus Curvularia, are also said to be suitable for carrying out the method. However, this generally does not provide any advantage to the method according to the invention. Growth is carried out in a suitable aerated culture medium and submerged culture under culture conditions commonly used for the microorganisms.
Substrate is then added to the culture (either dissolved in a suitable solvent or preferably in emulsified form) and fermented until maximum substrate conversion is achieved. Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide.
Emulsification of the substrate can be carried out, for example, by dissolving the substrate in finely divided form or in a water-miscible solvent (e.g. methanol, ethanol, acetone, glycol monoethyl ether, dimethylformamide or dimethyl sulfoxide) using conventional emulsification techniques. This can be carried out by jetting under highly turbulent water into (preferably demineralized) water containing the auxiliary agent. Suitable emulsifiers are nonionic emulsifiers, such as ethylene oxide adducts or fatty acid esters of polyglycols. Suitable emulsifiers include, for example, the commercially available wetting agents Tegin, Tagat, Tween and Span. Emulsification of the substrate can often increase substrate throughput and thus substrate concentration. However, it is of course also possible to use other methods known to fermenters to increase the substrate throughput in the process according to the invention. The optimal substrate concentration, substrate addition time and fermentation period depend on the structure of the substrate used and the type of microorganism used. The above-mentioned concentrations, addition times and magnitudes of the fermentation period generally required in microbiological steroid conversions have to be ascertained in each individual case by preliminary tests well known to those skilled in the art. Optionally followed by dehydrogenation of the general formula △ 4 -steroid saturated in the 1-position,
It can be carried out by microbiological as well as purely chemical methods. That is, △ 4 -steroids can be used, for example, in the Bacillus genus [e.g. Bacillus lentus] under customary conditions.
Or Bacillus sphaericus
sphaericus)] or Arthrobacter (Arthro-
Dehydrogenation can be carried out at the 1-position using cultured bacteria of the genus Arthrobacter (eg, Arthrobacter simplex). However, it is also possible to heat the Δ4 -steroid together with the oxidizing agents customary in such reactions, such as selenium dioxide or 2,3-dichloro-5,6-dicyanobenzoquinone in an inert solvent. It is therefore also possible to carry out Δ 1 -dehydrogenation. The process product obtained is easily the corresponding 11β,
It can be broken down into 17α,21-trihydroxysteroids. This decomposition is carried out under the conditions customary for hydrolysis or alcoholysis of acetals.
That is, the compound may be dissolved, for example, in a lower alcohol such as methanol or ethanol, or in an organic solvent containing water such as glycol monomethyl ether, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylphosphonic acid triamide, acetone, hydrochloric acid, sulfuric acid, phosphorous acid, etc. acids, mineral acids such as perchloric acid, sulfonic acids such as p-toluolsulfonic acid, strongly acidic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, acidic ion exchangers or boron trifluoride, zinc chloride, Decomposition can be effected by reaction with a Lewis acid such as zinc bromide or titanium tetrachloride. The new corticoids of the general formula are distinguished by a very good anti-inflammatory action when applied topically and have a very advantageous separation between the desired local action and undesirable systemic side effects: Local action can be measured by a vasoconstriction test. Vasoconstriction studies are performed on eight healthy subjects of both sexes who have not received topical corticosteroid therapy during the last two weeks. After removing the stratum corneum to the transparent layer from the subject's back (peeling with Tesafilm 20 to 40 times), 0.1 g of each preparation was
An area of 4 cm 2 area is applied without a covering bandage. Apply the toning agent sequentially, rotating it so that it is not applied to the same part of the skin each time. Vasoconstriction is judged visually by the experimenter after 4 and 8 hours according to the following effects: 1 = complete pallor, 2 = slight residual erythema, 3
= moderate erythema (intensity of redness in the center of peeled skin, untreated skin and intact skin);
4 = erythema with few bright areas, 5 = no pallor,
or enhanced erythema. Make individual judgments. Difluororthoron-21-valerianate (=6α,9α-difluoro-11β-hydroxy-16α-methyl-21-valeryloxy-1,4-pregnadiene-3,20
-dione=DEV). The difference △ between the DEV average effect obtained in each test order and the average effect of the test substance is determined in each case. A positive deviation △ indicates that the test substance is judged to be advantageous compared to DFV, and a negative deviation indicates that it is judged to be disadvantageous as well. The table below lists the active substances used during the treatment of subjects.
Test results obtained using preparations containing 0.1 ppm are listed. The systemic action of the compound can be determined by an edema test with an adjuvant: 0.5% Mycobacterium butyricum suspension to create inflammatory lesions in SPF rats weighing 130-150 g. (US
Difko) 0.1 ml was injected into the right hind leg of SPF rats weighing 130-150 g. Measure the rat's paw volume before injection. Measure the paw volume again 24 hours after injection to determine the degree of edema. Varying amounts of the test substance (dissolved in a mixture of 29% benzyl benzoate and 71% castor oil) are then applied orally or subcutaneously to the rats. Leg volumes are measured again after a further 24 hours. Control animals are treated similarly, except that they are injected with a benzyl benzoate-castor oil mixture without the test substance. Typically, from the leg volume obtained, the amount of test substance required to reduce the experimentally produced leg edema volume by 50% is determined. The table below lists the test formulations obtained, in which the substances according to the invention are compared with structurally very similar known corticoids which exist as commercial preparations.
【表】
新規化合物は、ガーレン式薬学において常用さ
れる担持剤と組合わせることにより、接触性皮膚
炎、種々の湿疹、神経皮膚症、紅皮症、火傷、外
陰及び肛門、痒症、酒、皮膚紅斑性痕瘡、乾癬、
扁平紅色及び疣状苔癬及び類似の皮膚疾患の局所
的治療のために適する。
特殊性医薬の調製は、常法で作用物質を適当な
添加剤と一緒に所望の適用形、例えば溶液、ロー
シヨン、軟膏、クリーム又は硬膏に代えることに
よつて行なわれる。このようにして調製された医
薬の場合作用物質の温度は適用形に依存する。ロ
ーシヨン及び軟膏の場合には好ましくは0.001%
〜1%の作用物質濃度が用いられる。
更に新規化合物は場合により常用の担持剤及び
助剤と組合わせることにより、アレルギー性気道
疾患、例えば気管枝喘息又は鼻カタルの治療に用
いられうる吸入剤の製造にも好適である。
更に新規コルチコイドは、好ましくは10〜200
mgの作用物質を含有しかつ経口的に適用されるカ
プセル、錠剤又は糖衣丸の形で又は用量位当り好
ましくは100〜500mgを含有し、直腸的に適用され
る懸濁液の形で、潰瘍性結腸炎及び肉芽腫性結腸
炎のようなアレルギー性腸管疾患の治療にも適し
ている。
次に実施例により本発明を詳述する。
例 1
(a) 3β,21−ジアセトキシ−17α−ヒドロキシ−
5−プレグネン−20−オン21.63gを、水を含
まない塩化メチン150mlと水を含まないホルム
アルデヒドジメチルアセタール100mlとの中に
溶かす。次にこの溶液を水で冷却しかつ五酸化
リン21.6gとケイ藻土43gとの混合物を入れて
1時間室温で撹拌する。次いで反応混合物を濾
過し、残留物を塩化メチレンで洗浄し、濾液に
PH値9の得られるまでトリエチルアミンを加え
かつ真空で蒸発濃縮する。残留物をメタノール
−塩化メチレンより再結晶させて融点182〜184
℃の3β,21−ジアセトキシ−17α−メトキシメ
トキシ−5−プレグネン−20−オン22.68gを
得る。
(b) 酵母エキス0.3%、コーンスチープ
(CornSteep)液0.3%及びデンプン糖0.2%を含
有する無菌培養液(PH=7.0に調節)1を含
む2のエルレンマイヤーフラスコに、フラボ
バクテリウム・デヒドロデゲナンス
(Flavobacterium dehydrogenans)
ATCC13930の乾燥培養菌を接種し、30℃で2
日間毎分175回転で振盪する。
同一培養液85mlを含む500mlのエルレンマイ
ヤーフラスコに、フラボバクテリウム・デヒド
ロゲナンス増殖培養菌10mlを接種し、30℃で7
時間毎分175回転で振盪する。次にこの培養物
にジメチルホルムアミド中の3β,21−ジアセ
トキシ−17α−メトキシメトキシ−5−プレグ
ネン−20−オン0.5gの無菌溶液5mlを加えて、
更に65時間30℃で毎分175回転で振盪する。発
酵後培養物より塩化エチレン100mlで2回抽出
を行ない、抽出物を真空で蒸発濃縮し、残留物
を酸化アルミニウムを媒体とするクロマトグラ
フイーによつて精製して、融点152〜153℃の21
−ヒドロキシ−17α−メトキシメトキシ−4−
プレグネン3,20−ジオン402mgを得る。
(c) グルコース2%及びコーンスチープ液2%を
含有する無菌培養液(PH=6.5に調節)1を
含む2のエルレンマイヤーフラスコに、クル
ブラリア・ルナータ(Curvularia lunata)
NRRL2380の乾燥培養菌の浮遊液を接種して、
30℃で60時間毎分175回転で振盪する。
コーンスチープ液1.0%及び大豆粉1.25%を
含有する無菌培養液(PH=6.2に調節)90mlを
含む500mlのエルレンマイヤーフラスコにクル
ブラリア・ルナータ増殖培養菌10mlを接種し、
30℃で7時間毎分175回転で振り混ぜる。次に
この培養物にジメチルホルムアミド中の21−ヒ
ドロキシ−17α−メトキシメトキシ−4−プレ
グネン−3,20−ジオン30mgを無菌溶液0.6ml
を加えて、更に65時間前記条件下に発酵を行な
う。
発酵培養物を例1bで記載したようにして後
処理して、融点180〜182℃の11β,21−ジヒド
ロキシ−17α−メトキシメトキシ−4−プレグ
ネン−3,20−ジオン27mgを得る。
(d) 11β,21−ジヒドロキシ−17a−メトキシメ
トキシ−4−プレグネン−3,20−ジオン2.5
gを、水を含まない塩化メチレン40ml中に溶か
し、0℃に冷却しかつ15分以内にアルゴン下に
塩化メチレン10ml中の四塩化チタン2.25mlの溶
液を加える。反応混合物を90分間室温で撹拌
し、次に塩化メチレン150ml及び炭酸水素ナト
リウムの飽和水溶液100mlを加え、15分間撹拌
し、有機相を分離し、洗浄して中性にし、硫酸
ナトリウムを介して脱水しかつ真空で蒸発濃縮
する。残留物をクロロホルムより再結晶させて
分解温度215℃の11β,17α,21−トリヒドロキ
シ−4−プレグネン−3,20−ジオン2.19gを
得る。
例 2
酵母エキス0.1%、コーンスチープ液0.5%、デ
ンプン糖0.1%を含有する無菌培養液(PH7.0に調
節)500mlを含む2のエルレンマイヤーフラス
コに、アルトロバクテル・シンプレクス
ATCC6946の乾燥培養菌の浮遊液を接種し、30℃
で48時間毎分190回転で振盪する。
前記の培養液90mlを含む500mlのエルレンマイ
ヤーフラスコに、アルトロバクテル・シンプレク
ス増殖培養菌10mlを接種し、30℃で6時間毎分
165回転で振盪する。次にこの培養物にジメチル
ホルムアミド中の11β,21−ジヒドロキシ−17α
−メトキシエトキシ−4−プレグネン−3,20−
ジオン50mgの無菌溶液を加えて、更に42時間発酵
させる。
発酵培養物を例1bで記載したようにして後処
理して、融点229/230〜231℃の11β,21−ジヒ
ドロキシ−17α−メトキシエトキシ−1,4−プ
レグナジエン−3,20−ジオン44.5mgを得る。
例 3
(a) 21−アセトキシ−17α−ヒドロキシ−4−プ
レグナン−3,20−ジオン50gを、ホルムアル
デヒドジエチルアセタール600ml及び塩化メチ
レン600mlで懸濁し、−30〜40℃に冷却する。五
酸化リン75gとケイ藻土150gとの混合物を撹
拌下に導入して、−30℃で30時間撹拌する。こ
の溶液を濾過して、トリエチルアミンで中性に
する。溶剤を留去した後もう一度メタノールと
一緒に蒸留を行ない、残留物をメタノールより
再結晶させる。21−アセトキシ−17α−エトキ
シメトキシ−4−プレグネン−3,20−ジオン
35.9gが得られ、もう一度再結晶させると137
〜139℃で融解する。
(b) コーンスチープ液1%、大豆粉1.25%を含有
する無菌培養液(PH6.2に調節)1を含む2
のエルレンマイヤーフラスコに、クルブラリ
ア・ルナータNRRL2380の乾燥培養菌の浮遊
液を接種し、30℃で72時間毎分175回転で振盪
する。
前記のような無菌培養液29を含む50の発酵
槽に、前記クルブラリア・ルナータ培養菌1を
接種し、30℃で24時間2m3/hで通気しながら培
養する。
前記のような無菌培養液36を含む50の発酵
槽に、クルブラリア・ルナータの予備発酵槽培養
菌4を接種し、30℃で10時間、2m3/hで通気
しかつ220回転/minで撹拌しつつ増殖させる。
次にこの培養物に、エチレングリコールモノメチ
ルエーテル200ml中の21−アセトキシ−17α−エ
トキシメトキシ−4−プレグネン−3,20−ジオ
ン10gを加える。10時間からPH値を65〜7.0に保
つ。更に4時間後にもう一回エチレングリコール
モノエチルエーテル200ml中の21−アセトキシ−
17α−エトキシメトキシ−4−プレグネン3,20
−ジオン10gを加え、更に23時間前記条件下に発
酵を行なう。
発酵培養物から3回塩化エチレン10で抽出を
行ない、次いで例1bに記載したようにして後処
理する。融点153〜154℃の11β,21−ジヒドロキ
シ−17α−エトキシメトキシ−4−プレグネン−
3,20−ジオン13.8gを得る。
例 4
(a) 21−アセトキシ−17α−ヒドロキシ−4−プ
レグネン−3,20−ジオン25gを、ホルムアル
デヒドジプロピルアセタール200ml及び塩化メ
チレン320mlで懸濁し、−20℃に冷却する。五酸
化リン49.3g及びケイ藻土97gより成る混合物
を撹拌下に導入して22時間−20℃で撹拌する。
溶液を濾過し、トリエチルアミンで中性にす
る。メチレンクロリドを真空で留去し、ホルム
アルデヒドジプロピルアセタール相を、油状析
出物よりデカンテーシヨンする。他の溶剤を真
空で留去した後融点145〜147℃の21−アセトキ
シ−17α−プロポキシメトキシ−4−プレグネ
ン−3,20−ジオン19gが結晶化する。
(b) 21−アセトキシ−17α−プロポキシメトキシ
−4−プレグネン−3,20−ジオン10gを、ツ
ウイン80 1g及び3倍量の水と一緒にジノ
(Dyno)ミキサーKDL型〔バツハオーフエン
(Bachofen)社、バーゼル在〕で粉砕する。こ
の粉砕物を、1%H2O2で少なくとも4時間滅
菌する。
クルブラリア・ルナータNRRL2380を、例
3bに記載したように、振盪フラスコ及び予備
発酵槽で培養し、メイン発酵槽で接種する。こ
の発酵槽を例3bで記載したようにセツトし、
同様に例3bで記載した条件により10時間培養
する。次のこの培養物に21−アセトキシ−17α
−プロポキシメトキシ−4−プレグネン−3,
20−ジオンの粉砕物を加え、更に44時間発酵さ
せ、この際PH値を6.4〜6.7に保つ。発酵培養物
を例3bで記載したように後処理して、融点
134/135〜136℃の11β,21−ジヒドロキシ−
17α−プロポキシメトキシ−4−プレグネン−
3,20−ジオン6.5gを得る。
例 5
(a) 21−アセトキシ−17α−ヒドロキシ−4−プ
レグネン−3,20−ジオン50gを、ホルムアル
デヒドブチルアセタール500ml及び塩化メチレ
ン500mlで懸濁し、−35℃に冷却する。五酸化リ
ン74g及びケイ藻土150gより成る混合物を撹
拌下に導入し、30時間−35℃で撹拌する。溶液
を濾過し、トリエチルアミンで中性にする。塩
化メチレンを真空で留去し、ホルムアルデヒド
ジブチルアセタール相を油状析出物よりデカン
テーシヨンする。他の溶剤の真空での留去後に
融点123.5〜124.5℃の21−アセトキシ−17α−
ブトキシメトキシ−4−プレグネン−3,20−
ジオン38.7gが結晶化する。
(b) 21−アセトキシ−17α−ブトキシメトキシ−
4−プレグネン−3,20−ジオン8gをツウイ
ン80 0.8gと一緒に例4bで記載したように粉砕
する。
クルブラリア・ルナータNRRL2380を、振
盪フラスコ、予備発酵及びメイン発酵槽で例
3bで記載したように培養し、発酵させる。メ
イン発酵槽の10時間の時点で基質を加え、更に
50時間発酵させる。
発酵培養物を例3bで記載したように後処理
して、融点79〜81℃の11β,21−ジヒドロキシ
−17α−ブトキシメトキシ−4−プレグネン−
3,20−ジオン3.7gを得る。
例 6
(a) 21−アセトキシ−6α−フルオル−17α−ヒド
ロキシ−4−プレグネン−3,20−ジオン
10.60gを、塩化メチレン265ml及びホルムアル
デヒドジメチルアセタール47.7mlに溶かす。五
酸化リン7.95gとケイ藻土15.9gとより成る混
合物を少しずつ加え、生じる混合物を90分間室
温で窒素下に撹拌する。この溶液を濾過し、ト
リエチルアミン2.1mlを加える。溶剤を留去し、
残留物をメタノールより再結晶させる。融点
161〜167℃の21−アセトキシ−6α−フルオル
−17α−メトキシメトキシ−4−プレグネン−
3,20−ジオン7.6gを得る。
(b) クルブラリア・ルナータNRRL2380を、例
3bで記載したようにして、振盪フラスコ、予
備発酵槽及びメイン発酵槽で培養する。メイン
発酵槽における10時間の時点でエチレングリコ
ールモノメチルエーテル100ml中の21−アセト
キシ−6α−フルオル−17α−メトキシメトキシ
−4−プレグネン−3,20−ジオン5gを加え
る。PH値をこの時点で6.5〜7.0に保つ。14時間
でもう一度エチレングリコールモノエチルエー
テル100ml中の21−アセトキシ−6α−フルオル
−17α−メトキシメトキシ−4−プレグネン−
3,20−ジオン5gを加え、更に26時間発酵を
行なう。
発酵培養物を、例3bで記載したようにして
後処理し、融点190〜192℃の11β,21−ジヒド
ロキシ−6α−フルオル−メトキシ−4−プレ
グネン−3,20−ジオン4.2gを得る。
例 7
(a) 3β,21−ジアセトキシ−17α−ヒドロキシ−
16β−メチル−5−プレグネン−20−オン43g
を、ホルムアルデヒドジメチルアセタール800
ml中に溶かし、−15℃に冷却する。五酸化リン
43gとケイ藻土86gとより成る混合物を少しず
つ加え、生じる混合物を15時間約−15℃で冷却
する。溶液を濾過し、トリエチルアミンで中性
にし、溶剤を真空で留去する。残留物をメタノ
ールより再結晶させて、融点117〜118℃の3β,
21−ジアセトキシ−17α−メトキシメトキシ−
16β−メチル−5−プレグネン−20−オン31.5
gを得る。
(b) フラボバクテリウム・デヒドロゲナンス
ATCC13930を例1bで記載したように培養し、
発酵させる。7時間の時点でこの培養物にジメ
チルホルムアミド中の3β,21−ジアセトキシ
−17α−メトキシメトキシ−16β−メチル−5
−プレグネン−20−オン0.2gの無菌溶液4ml
を加え、更に65時間振盪する。
発酵実施後に培養物を例1bで記載したよう
に後処理して、融点126/128〜129℃の21−ヒ
ドロキシ−17α−メトキシメトキシ−16β−メ
チル−4−プレグネン−3,20−ジオン163mg
を得る。
(c) クルブラリア・ルナータNRRL2380を、例
1cで記載したようにして培養し、発酵させる。
7時間の時点でこの培養物にジメチルホルムア
ミド中の21−ヒドロキシ−17α−メトキシメト
キシ−16β−メチル−4−プレグネン−3,20
−ジオン50mgの無菌溶液1mlを加えて、更に65
時間発酵を行なう。
発酵培養物を、例1bに記載したようにして
後処理して、融点204/205〜206℃の11β,21
−ジヒドロキシ−17α−メトキシメトキシ−
16β−メチル−4−プレグネン−3,20−ジオ
ン34.5mgを得る。
例 8
(a) 21−アセトキシ−17α−ヒドロキシ−4−プ
レグネン−3,20−ジオン38.85gを、ホルム
アルデヒドジイソプロピルアセタール235mlと
塩化メチレン500mlと一緒に撹拌し、−20℃に冷
却する。五塩化リン75gとケイ藻土150gとよ
り成る混合物を撹拌下に入れて−20℃で20時間
撹拌する。この混合物を濾過し、塩化メチレン
で洗浄し、トリエチルアミンでPH9にもたら
す。溶剤を真空で留去し、残留物を塩化メチレ
ンにとる。溶液を塩化ナトリウム半飽和溶液で
洗浄し、硫酸ナトリウムで脱水し、活性炭で処
理し、ケイ藻土により吸引しかつ真空で濃縮す
る。残留物にシリカゲルを媒体としてトルオー
ル−酢酸エステル混合物でクロマトグラフイー
を施す。21−アセトキシ−17α−イソプロポキ
シメトキシ−4−プレグネン−3,20−ジオン
35.8gが得られる。このものはペンタンで結晶
化すると融点111〜117℃を示す。
(b) クルブラリア・ルナータNRRL2380を、例
3bに記載したように、振盪フラスコ、予備発
酵槽及びメイン発酵槽で培養する。メイン発酵
槽での10時間の時点でエチレングリコールモノ
エチルエーテル240ml中の21−アセトキシ−
17α−イソプロポキシメトキシ−4−プレグネ
ン−3,20−ジオン12gを加える。この時点よ
りPH値を6.5〜7.5に保ち、更に15時間発酵を行
なう。
発酵培養物を、例3bに記載したように、後
処理して、11β,21−ジヒドロキシ−17α−イ
ソプロポキシメトキシ−4−プレグネン−3,
20−ジオン(融点71゜/73〜78℃)8.4gを得
る。
(c) アルトロバクテル・シンプレクスATCC6946
を、例2で記載したように、増殖フラスコ及び
発酵フラスコで培養する。6時間の時点で発酵
フラスコにエチレングリコールモノメチルエー
テル中の11β,21−ジヒドロキシ−17α−イソ
プロポキシメトキシ−4−プレグネン−3,20
−ジオン50mgの無菌溶液1mlを加え、更に42時
間発酵を行なう。
発酵培養物を、例1bに記載したように後処
理すると、11β,21−ジヒドロキシ−17α−イ
ソプロポキシメトキシ−1,4−プレグナジエ
ン−3,20−ジオン(融点58゜/63〜65℃)32
mgが得られる。[Table] The new compound can be used in combination with a carrier commonly used in Galen-style pharmacy to treat contact dermatitis, various types of eczema, neurodermatoses, erythroderma, burns, vulva and anus, pruritus, rosacea, Skin erythematous scars, psoriasis,
Suitable for the topical treatment of lichen planus and verrucous and similar skin diseases. The preparation of specialty medicines is carried out in the customary manner by substituting the active substances together with suitable additives into the desired application form, for example a solution, lotion, ointment, cream or plaster. In the case of medicaments prepared in this way, the temperature of the active substance depends on the form of application. Preferably 0.001% for lotions and ointments
An agent concentration of ~1% is used. Furthermore, the novel compounds are also suitable, optionally in combination with customary carriers and auxiliaries, for the preparation of inhalants which can be used in the treatment of allergic airway diseases, such as bronchial asthma or nasal catarrh. Further, the novel corticoid preferably has a concentration of 10 to 200
ulcers in the form of capsules, tablets or dragees containing mg of active substance and applied orally or in the form of a suspension containing preferably 100 to 500 mg per dose position and applied rectally. It is also suitable for the treatment of allergic intestinal diseases such as sexual colitis and granulomatous colitis. Next, the present invention will be explained in detail with reference to Examples. Example 1 (a) 3β,21-diacetoxy-17α-hydroxy-
21.63 g of 5-pregnen-20-one are dissolved in 150 ml of water-free methine chloride and 100 ml of water-free formaldehyde dimethyl acetal. The solution is then cooled with water and a mixture of 21.6 g of phosphorus pentoxide and 43 g of diatomaceous earth is added and stirred for 1 hour at room temperature. The reaction mixture was then filtered, the residue washed with methylene chloride and the filtrate
Add triethylamine until a pH value of 9 is obtained and evaporate in vacuo. The residue was recrystallized from methanol-methylene chloride to give a melting point of 182-184.
22.68 g of 3β,21-diacetoxy-17α-methoxymethoxy-5-pregnen-20-one are obtained. (b) Into two Erlenmeyer flasks containing one sterile culture medium (adjusted to pH = 7.0) containing 0.3% yeast extract, 0.3% CornSteep solution and 0.2% starch sugar, Flavobacterium dehydro degenans (Flavobacterium dehydrogenans)
Inoculated with dry culture of ATCC13930 and incubated at 30℃ for 2 hours.
Shake at 175 revolutions per minute for days. A 500 ml Erlenmeyer flask containing 85 ml of the same culture solution was inoculated with 10 ml of Flavobacterium dehydrogenans growth culture, and incubated at 30°C for 7 days.
Shake at 175 revolutions per minute. To this culture was then added 5 ml of a sterile solution of 0.5 g of 3β,21-diacetoxy-17α-methoxymethoxy-5-pregnen-20-one in dimethylformamide.
Shake at 175 revolutions per minute at 30°C for an additional 65 hours. After fermentation, the culture was extracted twice with 100 ml of ethylene chloride, the extract was evaporated and concentrated in vacuo, and the residue was purified by chromatography using aluminum oxide as a medium to obtain 21%
-Hydroxy-17α-methoxymethoxy-4-
402 mg of pregnene 3,20-dione is obtained. (c) Curvularia lunata in two Erlenmeyer flasks containing one sterile culture (adjusted to PH = 6.5) containing 2% glucose and 2% cornsteep broth.
Inoculate with suspension of dried culture of NRRL2380,
Shake at 175 revolutions per minute for 60 h at 30 °C. A 500 ml Erlenmeyer flask containing 90 ml of a sterile culture solution (adjusted to pH = 6.2) containing 1.0% corn steep liquid and 1.25% soybean flour was inoculated with 10 ml of Curvularia lunata growth culture;
Shake at 175 revolutions per minute for 7 hours at 30°C. This culture was then treated with 30 mg of 21-hydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione in 0.6 ml of a sterile solution in dimethylformamide.
was added and fermentation was continued under the above conditions for an additional 65 hours. The fermentation culture is worked up as described in Example 1b to obtain 27 mg of 11β,21-dihydroxy-17α-methoxymethoxy-4-pregnene-3,20-dione with a melting point of 180-182°C. (d) 11β,21-dihydroxy-17a-methoxymethoxy-4-pregnene-3,20-dione 2.5
g in 40 ml of water-free methylene chloride, cooled to 0° C. and added within 15 minutes under argon a solution of 2.25 ml of titanium tetrachloride in 10 ml of methylene chloride. The reaction mixture is stirred for 90 min at room temperature, then 150 ml of methylene chloride and 100 ml of a saturated aqueous solution of sodium bicarbonate are added, stirred for 15 min, the organic phase is separated, washed neutral and dried over sodium sulfate. and evaporate in vacuo. The residue was recrystallized from chloroform to obtain 2.19 g of 11β,17α,21-trihydroxy-4-pregnene-3,20-dione having a decomposition temperature of 215°C. Example 2 Into two Erlenmeyer flasks containing 500 ml of a sterile culture medium (pH adjusted to 7.0) containing 0.1% yeast extract, 0.5% cornsteep liquid, and 0.1% starch sugar, Arthrobacter simplex
Inoculated with suspension of dried culture of ATCC6946 and heated to 30°C.
Shake at 190 rpm for 48 hours. A 500 ml Erlenmeyer flask containing 90 ml of the above culture solution was inoculated with 10 ml of Arthrobacter simplex growth culture and incubated every minute for 6 hours at 30°C.
Shake at 165 rpm. This culture was then treated with 11β,21-dihydroxy-17α in dimethylformamide.
-methoxyethoxy-4-pregnene-3,20-
Add 50 mg of dione in a sterile solution and ferment for a further 42 hours. The fermentation culture was worked up as described in Example 1b to obtain 44.5 mg of 11β,21-dihydroxy-17α-methoxyethoxy-1,4-pregnadiene-3,20-dione with a melting point of 229/230-231°C. obtain. Example 3 (a) 50 g of 21-acetoxy-17α-hydroxy-4-pregnane-3,20-dione are suspended in 600 ml of formaldehyde diethyl acetal and 600 ml of methylene chloride and cooled to -30 to 40°C. A mixture of 75 g of phosphorus pentoxide and 150 g of diatomaceous earth is introduced with stirring and stirred at -30 DEG C. for 30 hours. The solution is filtered and neutralized with triethylamine. After distilling off the solvent, it is distilled once again together with methanol, and the residue is recrystallized from methanol. 21-acetoxy-17α-ethoxymethoxy-4-pregnene-3,20-dione
35.9g was obtained, and when recrystallized again, 137
Melts at ~139°C. (b) Sterile culture solution containing 1% corn steep liquid and 1.25% soy flour (adjusted to pH 6.2) 1 containing 2
An Erlenmeyer flask was inoculated with a suspension of a dry culture of Curvularia lunata NRRL2380 and shaken at 175 revolutions per minute at 30°C for 72 hours. The Curvularia lunata culture 1 was inoculated into 50 fermenters containing the sterile culture solution 29 as described above, and cultured at 30° C. for 24 hours with aeration at 2 m 3 /h. Fifty fermenters containing a sterile culture 36 as described above were inoculated with a prefermenter culture 4 of Curvularia lunata for 10 hours at 30° C., aerated at 2 m 3 /h and stirred at 220 revolutions/min. Propagate while doing so.
10 g of 21-acetoxy-17α-ethoxymethoxy-4-pregnene-3,20-dione in 200 ml of ethylene glycol monomethyl ether are then added to this culture. Keep the PH value between 65 and 7.0 from 10 hours. After another 4 hours, add 21-acetoxy- in 200 ml of ethylene glycol monoethyl ether.
17α-ethoxymethoxy-4-pregnene 3,20
- Add 10 g of dione and carry out fermentation under the above conditions for a further 23 hours. The fermentation culture is extracted three times with 10 ethylene chloride and then worked up as described in Example 1b. 11β,21-dihydroxy-17α-ethoxymethoxy-4-pregnene with a melting point of 153-154°C
13.8 g of 3,20-dione are obtained. Example 4 (a) 25 g of 21-acetoxy-17α-hydroxy-4-pregnene-3,20-dione are suspended in 200 ml of formaldehyde dipropyl acetal and 320 ml of methylene chloride and cooled to -20°C. A mixture of 49.3 g of phosphorus pentoxide and 97 g of diatomaceous earth is introduced with stirring and stirred for 22 hours at -20 DEG C.
Filter the solution and neutralize with triethylamine. The methylene chloride is distilled off in vacuo and the formaldehyde dipropyl acetal phase is decanted from the oily precipitate. After distilling off the other solvents in vacuo, 19 g of 21-acetoxy-17α-propoxymethoxy-4-pregnene-3,20-dione with a melting point of 145 DEG-147 DEG C. crystallizes. (b) 10 g of 21-acetoxy-17α-propoxymethoxy-4-pregnene-3,20-dione was mixed with 1 g of Twin 80 and 3 times the amount of water in a Dyno mixer KDL model [Bachofen, Crush it in Basel. The grind is sterilized with 1% H 2 O 2 for at least 4 hours. Curvularia lunata NRRL2380, e.g.
Culture in shake flasks and pre-fermenters and inoculate in the main fermenter as described in 3b. The fermenter was set up as described in Example 3b and
Cultivate for 10 hours under the same conditions as described in Example 3b. Next to this culture 21-acetoxy-17α
-propoxymethoxy-4-pregnene-3,
Add pulverized 20-dione and ferment for another 44 hours, keeping the pH value between 6.4 and 6.7. The fermentation culture was worked up as described in Example 3b to reduce the melting point
134/11β,21-dihydroxy at 135-136℃
17α-propoxymethoxy-4-pregnene-
6.5 g of 3,20-dione are obtained. Example 5 (a) 50 g of 21-acetoxy-17α-hydroxy-4-pregnene-3,20-dione are suspended in 500 ml of formaldehyde butyl acetal and 500 ml of methylene chloride and cooled to -35°C. A mixture of 74 g of phosphorus pentoxide and 150 g of diatomaceous earth is introduced with stirring and stirred for 30 hours at -35 DEG C. Filter the solution and neutralize with triethylamine. The methylene chloride is distilled off in vacuo and the formaldehyde dibutyl acetal phase is decanted from the oily precipitate. 21-acetoxy-17α- with a melting point of 123.5-124.5°C after distillation in vacuo of other solvents.
Butoxymethoxy-4-pregnene-3,20-
38.7 g of dione crystallizes. (b) 21-acetoxy-17α-butoxymethoxy-
8 g of 4-pregnene-3,20-dione are ground together with 0.8 g of Twin 80 as described in Example 4b. Examples of Curvularia lunata NRRL2380 in shake flask, pre-fermentation and main fermenter
Culture and ferment as described in 3b. At 10 hours in the main fermenter, add substrate and further
Ferment for 50 hours. The fermentation culture was worked up as described in Example 3b to give 11β,21-dihydroxy-17α-butoxymethoxy-4-pregnene-, melting point 79-81°C.
3.7 g of 3,20-dione are obtained. Example 6 (a) 21-acetoxy-6α-fluoro-17α-hydroxy-4-pregnene-3,20-dione
Dissolve 10.60 g in 265 ml of methylene chloride and 47.7 ml of formaldehyde dimethyl acetal. A mixture consisting of 7.95 g of phosphorus pentoxide and 15.9 g of diatomaceous earth is added in portions and the resulting mixture is stirred for 90 minutes at room temperature under nitrogen. Filter this solution and add 2.1 ml of triethylamine. Distill the solvent,
The residue is recrystallized from methanol. melting point
21-acetoxy-6α-fluoro-17α-methoxymethoxy-4-pregnene at 161-167℃
7.6 g of 3,20-dione are obtained. (b) Curvularia lunata NRRL2380, e.g.
Culture in shake flasks, pre-fermenters and main fermenters as described in 3b. At 10 hours in the main fermentor, 5 g of 21-acetoxy-6α-fluoro-17α-methoxymethoxy-4-pregnene-3,20-dione in 100 ml of ethylene glycol monomethyl ether are added. Keep the PH value between 6.5 and 7.0 at this point. 21-acetoxy-6α-fluoro-17α-methoxymethoxy-4-pregnene-17α-methoxymethoxy-4-pregnene in 100 ml of ethylene glycol monoethyl ether again in 14 hours.
Add 5 g of 3,20-dione and ferment for an additional 26 hours. The fermentation culture is worked up as described in Example 3b to obtain 4.2 g of 11β,21-dihydroxy-6α-fluoro-methoxy-4-pregnene-3,20-dione with a melting point of 190-192°C. Example 7 (a) 3β,21-diacetoxy-17α-hydroxy-
16β-methyl-5-pregnen-20-one 43g
, formaldehyde dimethyl acetal 800
ml and cooled to -15°C. phosphorus pentoxide
A mixture of 43 g and 86 g of diatomaceous earth is added in portions and the resulting mixture is cooled for 15 hours at about -15°C. The solution is filtered, neutralized with triethylamine and the solvent is removed in vacuo. The residue was recrystallized from methanol to give 3β, melting point 117-118℃.
21-diacetoxy-17α-methoxymethoxy-
16β-Methyl-5-pregnen-20-one 31.5
get g. (b) Flavobacterium dehydrogenans
ATCC13930 was cultured as described in Example 1b,
Ferment. At 7 hours, the culture was treated with 3β,21-diacetoxy-17α-methoxymethoxy-16β-methyl-5 in dimethylformamide.
-4 ml of a sterile solution of 0.2 g of pregnene-20-one
and shake for an additional 65 hours. After carrying out the fermentation, the culture was worked up as described in Example 1b to obtain 163 mg of 21-hydroxy-17α-methoxymethoxy-16β-methyl-4-pregnene-3,20-dione with a melting point of 126/128-129°C.
get. (c) Curvularia lunata NRRL2380, e.g.
Cultivate and ferment as described in 1c.
At 7 hours, the culture was treated with 21-hydroxy-17α-methoxymethoxy-16β-methyl-4-pregnene-3,20 in dimethylformamide.
- Add 1 ml of a sterile solution of 50 mg of dione and add 65
Ferment for hours. The fermentation culture was worked up as described in Example 1b to produce 11β,21 with a melting point of 204/205-206°C.
-dihydroxy-17α-methoxymethoxy-
34.5 mg of 16β-methyl-4-pregnene-3,20-dione are obtained. Example 8 (a) 38.85 g of 21-acetoxy-17α-hydroxy-4-pregnene-3,20-dione are stirred with 235 ml of formaldehyde diisopropyl acetal and 500 ml of methylene chloride and cooled to -20°C. A mixture of 75 g of phosphorus pentachloride and 150 g of diatomaceous earth is stirred at -20° C. for 20 hours. The mixture is filtered, washed with methylene chloride and brought to pH 9 with triethylamine. The solvent is removed in vacuo and the residue is taken up in methylene chloride. The solution is washed with half-saturated sodium chloride solution, dried over sodium sulfate, treated with activated charcoal, sucked through diatomaceous earth and concentrated in vacuo. The residue is chromatographed with a toluene-acetate mixture over silica gel. 21-acetoxy-17α-isopropoxymethoxy-4-pregnene-3,20-dione
35.8g is obtained. This product has a melting point of 111-117°C when crystallized with pentane. (b) Curvularia lunata NRRL2380, e.g.
Culture in shake flasks, pre-fermenters and main fermenters as described in 3b. 21-acetoxy- in 240 ml of ethylene glycol monoethyl ether at 10 hours in the main fermenter.
Add 12 g of 17α-isopropoxymethoxy-4-pregnene-3,20-dione. From this point on, the pH value is maintained at 6.5-7.5 and fermentation is continued for an additional 15 hours. The fermentation culture was worked up as described in Example 3b to give 11β,21-dihydroxy-17α-isopropoxymethoxy-4-pregnene-3,
8.4 g of 20-dione (melting point 71°/73-78°C) are obtained. (c) Arthrobacter simplex ATCC6946
are cultured in growth flasks and fermentation flasks as described in Example 2. At 6 hours, the fermentation flask was charged with 11β,21-dihydroxy-17α-isopropoxymethoxy-4-pregnene-3,20 in ethylene glycol monomethyl ether.
- Add 1 ml of a sterile solution of 50 mg of dione and carry out fermentation for a further 42 hours. The fermentation culture was worked up as described in Example 1b to produce 11β,21-dihydroxy-17α-isopropoxymethoxy-1,4-pregnadiene-3,20-dione (melting point 58°/63-65°C).
mg is obtained.
Claims (1)
素原子、フツ素原子、塩素原子又はメチル基を表
わし、 Wはメチレン基、エチリデン基又はビニリデン
基を表わし、 R1は炭素原子数1〜6を有するアルキル基を
表わす〕 で示される11β−ヒドロキシステロイドを製造す
るに当り、一般式XI: 〔式中X、W及びR1は前記のものを表わし、R4
はヒドロキシ基又は炭素原子数1〜6のアルカノ
イルオキシ基を表わす〕で示される11−デスオキ
システロイドを、クルブラリア属の培養菌で発酵
させ、得られた〓が単結合を表わす式の化合物
を、場合によつては1,2−位で脱水素化するこ
とを特徴とする前記11β−ヒドロキシステロイド
の製造方法。[Claims] 1. General formula: [In the formula] represents a single bond or double bond, X represents a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group, W represents a methylene group, an ethylidene group, or a vinylidene group, R 1 is the number of carbon atoms represents an alkyl group having 1 to 6] In producing the 11β-hydroxysteroid represented by the general formula XI: [In the formula, X, W and R 1 represent the above, and R 4
represents a hydroxy group or an alkanoyloxy group having 1 to 6 carbon atoms] is fermented with a cultured bacterium of the genus Curvularia, and the resulting compound of the formula in which 〓 represents a single bond, The method for producing 11β-hydroxysteroids, characterized in that dehydrogenation is carried out at the 1,2-position in some cases.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19782803661 DE2803661A1 (en) | 1978-01-25 | 1978-01-25 | Pregnane derivs. microbiological 11-beta-hydroxylation - using starting materials 17 alpha-substd. by an acetal group |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS54163564A JPS54163564A (en) | 1979-12-26 |
JPS6361000B2 true JPS6361000B2 (en) | 1988-11-28 |
Family
ID=6030586
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP660379A Granted JPS54163564A (en) | 1978-01-25 | 1979-01-25 | Novel pregnane 11 betaahydroxysteroid substituted in 177position*its manufacture and manufacture of antiiinflammatory medicine containing it and other sterids |
Country Status (5)
Country | Link |
---|---|
JP (1) | JPS54163564A (en) |
DE (1) | DE2803661A1 (en) |
HU (1) | HU185778B (en) |
PL (1) | PL121296B1 (en) |
ZA (1) | ZA79318B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3227312A1 (en) * | 1982-07-19 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW 6.16 DIMETHYL CORTICOIDS, THEIR PRODUCTION AND USE |
US4588683A (en) * | 1984-02-06 | 1986-05-13 | Eastman Kodak Company | Method of preparing 11β, 17α, 20, 21-tetrahydroxy steroids and corresponding 11β, 17α, 21-trihydroxy-20-oxo steroids |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51115457A (en) * | 1974-03-27 | 1976-10-12 | Plurichemie Anstalt | 166methyll9 alphaa halosteroid derivatives |
-
1978
- 1978-01-25 DE DE19782803661 patent/DE2803661A1/en not_active Withdrawn
-
1979
- 1979-01-23 PL PL1979222270A patent/PL121296B1/en unknown
- 1979-01-24 HU HU79SCHE672A patent/HU185778B/en not_active IP Right Cessation
- 1979-01-25 JP JP660379A patent/JPS54163564A/en active Granted
- 1979-01-25 ZA ZA79318A patent/ZA79318B/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS51115457A (en) * | 1974-03-27 | 1976-10-12 | Plurichemie Anstalt | 166methyll9 alphaa halosteroid derivatives |
Also Published As
Publication number | Publication date |
---|---|
PL222270A1 (en) | 1980-10-20 |
HU185778B (en) | 1985-03-28 |
JPS54163564A (en) | 1979-12-26 |
PL121296B1 (en) | 1982-04-30 |
ZA79318B (en) | 1980-01-30 |
DE2803661A1 (en) | 1979-07-26 |
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